This application is the U.S. national phase of PCT International Application No. PCT/GB98/01100, filed Apr. 15, 1998, which claims priority to South African application No. 97/3201, filed Apr. 15, 1997.
THIS INVENTION relates to steroidal glycosides, to compositions containing such steroidal glycosides and to a new use for these steroidal glycosides and the compositions containing them. The invention further relates to a method of extracting and isolating these steroidal glycosides from plant material, to a method of synthetically producing these steroidal glycosides, and to the products of such an extraction and such a synthesis process.
In a particular application, the invention relates to an appetite suppressant agent, to a process for synthetically producing the appetite suppressant agent, to a process for extracting the appetite suppressant agent from plant material, to an appetite suppressant composition containing the appetite suppressant agent, and to a method of suppressing an appetite.
According to the invention, there is provided a process for preparing an extract of a plant of the genus Trichocaulon or of the genus Hoodia, the extract comprising an appetite suppressant agent, the process including the steps of treating collected plant material with a solvent to extract a fraction having appetite suppressant activity, separating the extraction solution from the rest of the plant material, removing the solvent from the extraction solution and recovering the extract. The extract so recovered may be further purified, eg by way of suitable solvent extraction procedures.
The invention also provides a plant extract made of plants of the group comprising the genus Trichocaulon and the genus Hoodia and having appetite suppressant activity.
The extract may be prepared from plant material such as the stems and roots of said plants of the genus Trichocaulon or of the genus. Hoodia. The genus Trichocaulon and the genus Hoodia include succulent plants growing in arid regions such as are found in Southern Africa. In one application of the invention, the active appetite suppressant extract is obtained from the species Trichocaulon piliferum. The species Trichocaulon officinale may also be used to provide an active appetite suppressant extract. In another application of the invention, the active appetite suppressant extract may be obtained from the species Hoodia currorii, Hoodia gordonii or Hoodia lugardii. Bioassays conducted by the Applicant on rats have indicated that certain of the extracts possess appetite suppressant activity.
The plant material may be homogenised in the presence of a suitable solvent, for example, a methanol/methylene chloride solvent, by means of a device such as a Waring blender. The extraction solution may then be separated from the residual plant material by an appropriate separation procedure such as, for example, filtration or centrifugation. The solvent may be removed by means of the rotary evaporator, preferably in a water bath at a temperature of 60xc2x0 C. The separated crude extract may then be further extracted with methylene chloride and water before being separated into a methylene chloride extract and a water extract. The methylene chloride extract may have the solvent removed preferably by means of evaporation on a rotary evaporator and the resultant extract may be further purified by way of a methanol/hexane extraction. The methanol/hexane extraction product may then be separated to yield a methanol extract and a hexane extract. The methanol extract may be evaporated to remove the solvent in order to yield a partially purified active extract.
The partially purified active extract may be dissolved in methanol, and may be further fractionated by column chromatography, employing silica gel as an adsorption medium and a chloroform/30% methanol mixture as an eluent. A plurality of different fractions may be obtained, and each may be evaluated, by suitable bioassaying procedures, to determine the appetite suppressant activity thereof.
A fraction having appetite suppressant activity may preferably be further fractionated such as by column chromatography using silica gel as an adsorption medium and a 9:1 chloroform:methanol solvent, and the resultant sub-fractions bioassayed for their appetite suppressant activity. A sub-fraction displaying appetite suppressant activity may, if desired, be further fractionated and purified, conveniently using a column chromatographic procedure with silica gel as the adsorption medium and a 9:1 ethylacetate:hexane solvent. The resultant purified fractions may again be evaluated by suitable bioassay procedures for their appetite suppressant activity.
The Applicant has found that at least one such purified fraction has good appetite suppressant activity, and the active principle in the fraction was identified by conventional chemical techniques including nuclear magnetic resonance, and was found to be a compound of the structural formula 
In accordance with S.I. nomenclature, the active principle (1) is the compound 3-0-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-0-tigloyloxy-14-hydroxy-14xcex2-pregn-50-en-20-one (C47H74O15 M+878).
According to another aspect of the invention, there is provided a process for preparing an extract of a plant of the genus Trichocaulon or of the genus Hoodia, the extract comprising an appetite suppressant agent, the process including the steps of pressing collected plant material to separate sap from solid plant material and recovering the sap free of the solid plant material to form the extract.
The extract may be dried to remove moisture, e.g. by spray-drying, freeze-drying or vacuum drying, to form a free-flowing powder.
The invention extends to a composition having appetite suppressant activity comprising an extract as described above.
The composition may be admixed with a pharmaceutical excipient, diluent or carrier and optionally it is prepared in unit dosage form.
The invention also extends to the use of an extract as described above in the manufacture of a medicament having appetite suppressant activity, to an extract as described above for use as a medicament having appetite suppressant activity, and to a method of suppressing an appetite by administering to a human or animal an effective dosage of a composition as described above.
Compound (1) is a novel compound and the invention extends to compound (1) and certain analogues or derivatives of this steroidal trisaccharide having appetite suppressant properties. The molecules chosen as the analogues or derivatives are intended to affect the properties of the steroidal trisaccharide with the aim of increasing the activity of the active ingredient. The following effects were taken into consideration when the analogues were chosen:
(i) Hydrophobic interactions and lipophilicity
Functional group modifications of the active molecule is intended to change the hydrophobicity and lipophilicity of the molecule. Increased lipophilicity has been shown to correlate with increased biological activity, poorer aqueous solubility, increased detergency/cell lysis, increased storage in tissues, more rapid metabolism and elimination, increased plasma protein binding and faster rate of onset of action.
(ii) Electronic properties and ionization constants
Functional group modification of the molecule is also intended to change the acidity and basicity which would have a major role in controlling the transport of the compound to its site of action and the binding at this target site.
(iii) Hydrogen bonding
Functional group modifications of carboxyl and carbonyl groups in the active molecule are intended to change the interactions between the proteins in biological systems and the chemically modified functional groups.
(iv) Steric parameters
The purpose of changing the steric features of the molecule is to increase binding to its receptor and thus increase its biological activity.
The following chemical modifications to the molecule are intended to affect the hydrophobicity and lipophilicity electronic properties, hydrogen bonding and steric parameters on the molecule:
a) Chemical modification of the C-12 group and ester functionality;
b) Chemical modification of the 5,6-double bond, e.g. hydrogenation and migration;
c) Chemical modification of the C-20 carbonyl and C-17 acetyl group;
d) Chemical modification of the xe2x80x9cDxe2x80x9d ring of the steroid or aglycone ring;
e) Modification of the carbohydrates of the trisaccharide moiety.
Accordingly, the invention provides a compound having the general structural formula 
in which R=alkyl;
R1xe2x95x90H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2xe2x95x90H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
and in which the broken lines indicate the optional presence of a further bond between C4-C5 or C5-C6.
The invention also provides a compound as described above wherein there is a further bond between C5-C6, R=methyl, R1=tigloyl, R2=3-0-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl] and having the structural formula. 
Further active analogues or derivatives of the appetite suppressant compound (1) in accordance with the invention are compounds having the following structural formulae: 
in which R=alkyl; and
R1xe2x95x90H or benzoyl, or, tigloyl, or any other organic ester group 
in which R=alkyl; and
R1xe2x95x90H, or tigloyl, or benzoyl, or any other organic ester group 
in which R=alkyl; and
R1xe2x95x90H, or tigloyl, or benzoyl, or any other organic ester group 
in which R=alkyl; and
R1xe2x95x90H, or tigloyl, or benzoyl, or any other organic ester group 
in which R=alkyl;
R1xe2x95x90H, or tigloyl, or benzoyl, or any other organic ester group. 
in which R=alkyl; and
R1xe2x95x90H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2xe2x95x90H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
and in which the broken lines indicate the optional presence of a further bond between C4-C5 or C5-C6. 
in which R=alkyl; and
R1xe2x95x90H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2xe2x95x90H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
and in which the broken lines indicate the presence of a further bond between C4-C5 or C5-C6. 
in which R=alkyl; and
R1xe2x95x90H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2xe2x95x90H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
and in which the broken lines indicate the optional presence of a further bond between C4-C5 or C5-C6. 
in which R=alkyl; and
R1xe2x95x90H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2xe2x95x90H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
and in which the broken lines indicate the optional presence of a further bond between C4-C5, C5-C6 or C14-C15. 
in which R=alkyl; and
R1xe2x95x90H, alkyl, tigloyl, benzoyl, any other organic ester group;
R2xe2x95x90H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
and in which the broken lines indicate the optional presence of a further bond between C4-C5, C5-C6 or C14-C15. 
in which R=alkyl; and
R1xe2x95x90H, alkyl, tigloyl, benzoyl, any other organic ester group;
R2xe2x95x90H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
and in which the broken lines indicate the optional presence of a further bond between C4-C5, C5-C6 or C14-C15; and
R3xe2x95x90H, alkyl, aryl, acyl, or glucoxy. 
in which Rxe2x95x90H, alkyl, aryl or any steroid possessing a C14 beta hydroxy group, or a C12 beta hydroxy functionality, or a C17 acyl group, or a C5-C6 olefin, or combinations thereof.
The invention still further extends to a process for synthetically producing a compound having appetite suppressant activity.
The process uses a steroid as a starting material (or intermediate or precursor), the steroid having the chemical formula 
The steroid (15) can be prepared from a compound having the formula (22) by a process which includes the steps of
(i) treating progesterone having the formula 
xe2x80x83with the micro-organism Calonectria decora to produce a compound 12xcex2, 15xcex1-dihydroxy progesterone of the formula 
(ii) treating compound (17) with tosyl chloride and pyridine to produce a compound 12xcex2-hydroxy-15xcex1-(p-toluene sulfonyl)-progesterone of the formula 
(iii) treating the compound (18) with collidine at 150xc2x0 C. to produce a compound 12xcex2-hydroxy-xcex944-progesterone of the formula 
(iv) treating the compound (19) with acetyl chloride and acetic anhydride at 120xc2x0 C., to produce a compound 3,12xcex2-diacetoxypregna-3,5,14-trien-20-one of the formula 
(v) treating the compound (20) with ethylene glycol and a catalytic amount of p-toluene sulphonic acid, to produce a compound 3,12xcex2-diacetoxy-20,20-ethylenedioxypregna-3,5,14-triene of the formula 
(vi) treating the compound (21) with NaBH4 to produce a compound 3xcex2, 12xcex2-dihydroxy-20,20-ethylenedioxypregna-5,14-diene-12-acetate of the formula 
In a first alternative procedure, a process for the preparation of steroid (15) according to the invention includes the steps of
(a) treating compound (22) with a reducing agent, e.g. LiAlH4, to produce a compound 3xcex2, 12xcex2-dihydroxy-20,20-ethylenedioxypregna-5,14-diene of the formula 
(b) treating compound (23) with N-bromoacetamnide (NBA) and a base, e.g. pyridine, to produce a compound 3xcex2, 1262 -dihydroxy-14,15-epoxy-20,20-ethylenedioxypregn-5-ene of the formula 
(c) treating compound (24) with a reducing agent, e.g.
LiAlH4, e.g. with refluxing, to produce a compound 3xcex2, 12xcex2, 14xcex2-trihydroxy-20,20-ethylenedioxypregn-5-ene of the formula 
and (d) treating compound (25) with an acid, e.g. acetic acid, and water to produce the steroid intermediate compound 3xcex2, 12xcex2, 14xcex2-trihydroxypregn-5-ene (15).
Reaction Scheme A depicts the procedure for the preparation of steroid intermediate (15) from compound (22) according to xe2x80x9cthe first alternative procedurexe2x80x9d of the invention (and includes the preparation of compound (22) from compound (16) for illustrative purposes). 
In a second alternative procedure, a process for the preparation of steroid (15) according to the invention includes the steps of
(a) treating compound (22) (3xcex2, 12xcex2-dihydroxy-20,20-ethylenedioxypregna-5,14-diene-12-acetate) with p-toluenesulfonyl chloride and a base, e.g. pyridine, to produce a compound 3xcex2, 12xcex2-dihydroxy-20,20-ethylenedioxypregna-5,14-diene-3-tosyl-12-acetate of the formula 
(b) treating compound (26) with potassium acetate in a solvent, e.g. acetone, to produce a compound 6xcex2, 12xcex2-dihydroxy-20,20-ethylenedioxy-3,5xcex1-cyclopregnan-14-ene-12-acetate of the formula 
(c) treating the compound (27) with a reducing agent, e.g.
LiAlH4, and e.g. tetrahydrofuran, to produce a compound 6xcex2, 12xcex2-dihydroxy-20,20-ethylenedioxy-3,5xcex1-cyclopregnan-14-ene of the formula 
(d) treating the compound (28) with N-bromoacetamide, optionally acetic acid, and a base, e.g. pyridine, to produce a compound 6xcex2, 12xcex2-dihydroxy-20,20-ethylenedioxy-14,15-epoxy-3,5xcex1-cyclopregnane of the formula 
(e) treating the compound (29) with a reducing agent, e.g. LiAlH4, and e.g. tetrahydrofuran, to produce a compound 6xcex2, 12xcex2, 14xcex2-trihydroxy-20,20-ethylenedioxy-3,5xcex1-cyclopregnane of the formula 
and (f) treating compound (30) with an acid, e.g. hydrochloric acid, and a solvent e.g. acetone, to produce compound (15).
Reaction Scheme B shows the procedure for the preparation of steroid intermediate (15) from compound (22) according to xe2x80x9cthe second alternative procedurexe2x80x9d of the invention. 
Compound (I) may be synthesized from a first carbohydrate intermediate in the form of an activated monosaccharide cymarose moiety, which can be prepared from a compound having the formula (36). Compound (36) can be prepared by a process which includes the steps
(i) treating methyl-xcex1-D-glucose having the formula 
xe2x80x83with benzaldehyde and zinc chloride to produce a compound methyl-4,6-0-benzylidene-xcex1-D-glucopyranoside of the formula 
(ii) treating the compound (32) with tosyl chloride and pyridine at 0xc2x0 C., to produce a compound methyl-4,6-0-benzylidene-2-0-tosyl-xcex1-D-glucopyranoside of the formula 
(iii) treating the compound (33) with NaOMe at 100xc2x0 C. to produce a compound methyl 4,6-0-benzylidene-3-0-methyl-xcex1-D-altropyranoside of the formula 
(iv) treating the compound (34) with N-bromosuccinamide (NBS) to produce a compound methyl 6-bromo-4-0-benzoyl-3-0-methyl-6-deoxy-xcex1-D-altropyranoside of the formula 
and (v) treating the compound (35) with NaBH4 and NiCl2, to produce a compound methyl 4-0-benzoyl-3-0-methyl-6-deoxy-xcex1-D-altropyranoside of the formula 
The invention extends to a process for the preparation of a carbohydrate intermediate in the form of an activated monosaccharide cymarose moiety which includes the steps of
(i) treating the compound (36) with PhSSiMe3, ZnI2 and Bu4+Ixe2x88x92 to produce a compound 4-0-benzoyl-3-0-methyl-6-deoxy-xcex1xcex2-D-phenylthioaltroside of the formula 
(ii) optionally treating the compound (37) with diethylaminosulphur trifluoride (DAST), e.g. at 0xc2x0 C., to produce a compound 4-0-benzoyl-3-0-methyl-2-phenylthio-2,6-dideoxy-xcex1xcex2-D-fluorocymaropyranoside having the formula 
or (iii) optionally, treating the compound (37) with t-butyldimethylsilylchloride and imidazole in a solvent, e.g. pyridine, to produce 4-0-benzoyl-3-0-methyl-2-0-t-butyldimethylsilyl-xcex1xcex2-D-phenylthioaltroside having the formula 
xe2x80x83in which Z=TBDMS=t-butyldimethylsilyl
and (iv) treating the compound (39) with a base, e.g. sodium methoxide, to produce 3-0-methyl-2-0-t-butyldimethylsilyl-xcex1xcex2-D-phenylthioaltroside having the formula 
in which Z=TBDMS=t-butyldimethylsilyl.
Reaction Scheme C shows the procedure for the synthesis of the activated monosaccharide cymarose moiety (40) from compound (36) according to the invention (and includes the preparation of compound (36) from compound (31) for illustrative purposes). 
The synthesis of compound (1) may also involve a second carbohydrate intermediate in the form of an activated monosaccharide thevetose moiety, which can be prepared from a compound having the formula (47). Compound (47) can be prepared by a process which includes the steps of
(i) treating xcex1-D-glucose having the formula 
xe2x80x83with acetone and sulphuric acid to produce a compound 1,2:5,6-di-0-isopropylidene-xcex1-D-glucofuranose of the formula 
(ii) treating the compound (42) with NaH and MeI to produce a compound 1,2:5,6-Di-0-isopropylidene-3-0-methyl-xcex1-D-glucofuranose of the formula 
(iii) treating the compound (43) with acetic acid to produce a compound 3-0-methyl-xcex1xcex2-D-glucopyranose of the formula 
(iv) treating the compound (44) with methanol and hydrochloric acid to produce a compound methyl 3-0-methyl-xcex1xcex2-D-glucopyranoside having the formula 
(v) treating the compound (45) with benzaldehyde and zinc chloride to produce a compound methyl 4,6-0-benzylidene-3-0-methyl-xcex1xcex2-glucopyranoside having the formula 
(vi) treating the compound (46) with N-bromosuccinamide, nickel chloride and sodium borohydride to produce a compound methyl 4-0-benzoyl-3-0-methyl-6-deoxy-xcex1xcex2-glucopyranoside having the formula 
The invention extends to a process for the preparation of an activated monosaccharide thevetose moiety which includes the steps of
(i) treating the compound (47) with phenylthiotrimethylsilane and trimethylsilyltrifluoromethanesulphonate to produce a compound 4-0-benzoyl-3-0-methyl-1-phenylthio-6-deoxy-xcex1xcex2-glucopyranoside having the formula 
(ii) treating the compound (48) with pivaloyl chloride and a solvent, e.g. pyridine, to produce a compound 4-0-benzoyl-3-0-methyl-2-0-pivaloyl-1-phenylthio-6-deoxy-xcex1xcex2-glucopyranoside having the formula 
and (iii) treating the compound (49) with a brominating agent, e.g. N-bromosuccinimnide, and diethylaminosulphur trifluoride to produce a comnpound 4-0benzoyl-3-0-methyl-2-0-pivaloyl-1-stereo-isomers having the formula 
Reaction Scheme D shows the procedure for the synthesis of the activated monosaccharide thevetose moiety (50(A) and 50(B)) from compound (48) according to the invention (and includes the preparation of compound (47) from compound (41) for illustrative purposes) 
According to a still further aspect of the invention there is provided a process of synthetically producing a compound of the formula (1) and analogues and derivatives thereof which includes the steps of synthesising a suitable steroid intermediate or precursor and coupling the required number of suitable monosaccharides with the steroid intermediate.
The invention also provides a process of coupling a monosaccharide cymarose with the steroid intermediate, which includes the steps of
(i) reacting a cymarose moiety (38) with a steroid intermediate (15), e.g. at xe2x88x9215xc2x0 C., and in the presence of tin chloride, in a solvent, e.g. ether, to produce a compound 3-0-[4-0-benzoyl-2-phenylthio-xcex2-D-cymaropoyranosyl]-12,14-xcex2-dihydroxy-pregn-5-ene-20-one of the formula 
and (ii) treating the compound (51) with tiglic acid chloride in pyridine and thereafter with a base, e.g. NaOMe, to produce a compound 3-0-[-2-phenylthio-xcex2-D-cymaropyranosyl]-12xcex2-tigloyloxy-14-hydroxy-14xcex2-pregn-5-ene-20-one of the formula 
The invention extends to a process which includes coupling a monosaccharide cymarose moiety to a monosaccharide thevetose moiety and coupling the resultant disaccharide with the combined steroid product (52) to form compound (1).
The process of coupling the monosaccharide cymarose moiety to the monosaccharide thevetose moiety and coupling the resultant disaccharide to the combined steroid product (52) may include the steps of (4) coupling a selectively protected cymarose moiety (40) and a selectively protected thevetose moiety (50 A) using tin chloride (SnCl2) and silver trifluoromethanesulphonate, e.g. at xe2x88x9215xc2x0 C., to produce a compound of the formula 
xe2x80x83in which Z=TBDMS=t-butyldimethylsilyl
(ii) treating compound (53) with tetrabutylammoniumfluoride to produce a compound of the formula 
(iii) treating compound (54) with diethylaminosulphur trifluoride, e.g. at 0xc2x0 C., to produce a compound of the formula 
(iv) reacting compound (55) with compound (52) to produce a compound of the formula 
and (v) treating compound (56) in a Raney-Nickel reaction and thereafter with a base, e.g. NaOMe, to produce compound (1) as described above.
Reaction Scheme E shows the procedure for the synthesis of intermediates (52) and (55) and coupling them to form compound (56). 
According to the invention, an alternative process is provided which includes coupling cymarose and thevetose moieties to form a trisaccharide and coupling the trisaccharide onto a steroid derivative to form a compound of the formula (1).
The process of forming the trisaccharide and coupling the resultant trisaccharide to a steroid derivative may include the steps of
(i) coupling a selectively protected cymarose moiety (40) and compound (45) using tin (II) chloride, AgOTf, Cp2ZrCl2 to produce a compound of the formula 
xe2x80x83in which Z=TBDMS=t-butyldimethylsilyl
(i) treating compound (57) with tetrabutylammonium luoride and diethylaminosulphur trifluoride to produce a trisaccharide compound having the formula 
and (iii) coupling the trisaccharide (58) with a steroid intermediate of the formula 
xe2x80x83using tin (II) chloride, AgOTf, Cp2ZrCl2 to produce compound (1).
The steroid intermediate (59) may he produced by treating steroid (15) with tiglic acid chloride.
Reaction Scheme F shows the procedure for the synthesis of the trisaccharide (58) and the synthesis of compound (1) by coupling the trisaccharide (58) with the steroid intermediate (59). 
The intermediates (23), (24), (25), (27), (28), (29), (30), (37), (38), (39), (40), (48), (49), (50), (51), (53), (54), (55), (56), (57) and (58) described above are novel compounds and the invention extends to these compounds as such.
Compound (1), 3-0-[-xcex2-D-thevecopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-0-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one, and various analogues and derivatives thereof have been found to have appetite suppressing activity.
The invention extends also to a composition or formulation having appetite suppressant activity, in which the active ingredient is an extract obtained from a plant of the genus Trichocaulon or the genus Hoodia.
The active ingredient may be a compound of the formula (1), extracted from a plant of the genus Trichocaulon or Hoodia or a derivative thereof. The plant may be of the species Trichocaulon officinale or Trichocaulon piliferum, or the species Hoodia currorii, Hoodia gordonii or Hoodia lugardii. 
The invention extends also to a composition or formulation having appetite suppressant activity, in which the active ingredient is a synthetically produced compound of the formula (1) or a derivative or analogue thereof, as hereinbefore set out with reference to compounds (2) to (14).
According to another aspect of the invention there is provided a method of suppressing an appetite by administering to a human or animal a suitable dosage of an appetite suppressant agent comprising an extract of a plant of the genus Trichocaulon or Hoodia. The extract may be incorporated in a composition or formulation including also pharmaceutically acceptable other ingredients.
The appetite suppressant agent may be an isolated natural chemical or a synthetic chemical compound of the formula: 
or derivatives or analogues thereof, as set out before.
The appetite suppressant composition or formulation may consist of the appetite suppressant agent admixed with a Apharmaceutical excipient, diluent or carrier. Other suitable additives, including a stabilizer and such other ingredients as may be desired may be added.
The invention extends to the use of compound (1) or its derivatives or analogues in the manufacture of a medicament having appetite suppressant activity.
The invention further extends to compound (1), or its derivatives or analogues as set out before, for use as a medicament having appetite suppressant activity.
A method of suppressing an appetite by administering to a human or animal an effective dosage of a composition as described above is also provided.
A method has been described herein for extracting a steroidal glycoside having appetite suppressant activity from plant material obtained from a plant of the Trrichocaulon or Hoodia genus. The invention thus extends to an extract obtained from plant material of the Trichocaulon or Hoodia genus and containing a substantially pure steroidal glycoside of formula (1).
The invention extends also to a foodstuff or a beverage containing an effective quantity of the steroidal glycoside of the formula (1), or its derivatives or analogues as set out before, to have an appetite suppressant effect when ingested.
Molecular genetic studies have led to a considerable increase in the understanding of the regulation of appetite, satiety and bodyweight. These studies have revealed numerous central regulatory pathways, mediated by a number of neuropeptides. The maintenance of a normal body weight is achieved by an intricate balance between energy intake, food consumption, and energy expenditure. Energy homeostasis is subject to a wide range of influences, ultimately controlled by the brain. The different signals include such things as sense of smell and taste and gastro-intestinal signals such as distension of the gastro-intestinal tract, chemical signals to the gastric mucosa and blood-borne metabolites such as fatty acids and glucose.
Centrally, neuropeptide xe2x80x9cYxe2x80x9d (NPY) which is negatively regulated by leptin, has been established as one of the positive regulators of feeding behaviour. Expression of the endogenous antagonist for melanocortin receptors has also been shown to be the basis for obesity in a particular model (the ob/ob mouse). Indeed deficiency at the MC4 melanocortin receptor completely replicates the obesity syndrome. Other mediators which have been shown to have roles in the energy balance include bombesin, galonin and glucagon-like peptide-1.
Without being bound by theory, the Applicant believes that compound (1) and its analogues as described above act as an agonist of the melanocortin 4 receptor. The effect of this is to regulate NPY but also to increase cholecystokinin. The effect of cholecystokinin amongst other things is to inhibit gastric emptying.
Accordingly, the invention extends to a composition having appetite suppressant activity comprising a melanocortin 4 receptor agonist.
The agonist may be an extract or compound as previously described, in particular the compound of formula (1) The composition may be admixed with a pharmaceutical excipient, diluent or carrier and is optionally prepared in unit dosage form.
The invention still further extends to the use of a melanocortin 4 receptor agonist in the manufacture of a medicament having appetite suppressant activity, to a melanocortin 4 receptor agonist for use as a medicament having appetite suppressant activity, to a method of suppressing an appetite by administering to a human or animal an effective dosage of a composition comprising a melanocortin 4 agonist as described above, and to the use of a melanocortin 4 receptor agonist to suppress the appetite of and/or to combat obesity in a human or animal.
The invention and its efficacy will now be further described, without limitation of the scope of the invention, with reference to the following examples and drawings.